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1.
Safety of Vitamin K in mechanical heart valve patients with supratherapeutic INR: A systematic review and meta-analysis
Sapapsap B, Srisawat C, Suthumpoung P, Luengrungkiat O, Leelakanok N, Saokaew S, Kanchanasurakit S
Medicine. 2022;101(36):e30388
Abstract
BACKGROUND Patients who had mechanical heart valves and an international normalized ratio (INR) of >5.0 should be managed by temporary cessation of vitamin K antagonist. This study aimed to investigate the safety of low-dose vitamin K1 in patients with mechanical heart valves who have supratherapeutic INR. METHODS CINAHL, Cochran Library, Clinical trial.gov, OpenGrey, PubMed, ScienceDirect, and Scopus were systematically searched from the inception up to October 2021 without language restriction. Studies comparing the safety of low-dose vitamin K1 treatment in patients with placebo or other anticoagulant reversal agents were included. We used a random-effect model for the meta-analysis. Publication bias was determined by a funnel plot with subsequent Begg's test and Egger's test. RESULTS From 7529 retrieved studies, 3 randomized control trials were included in the meta-analysis. Pooled data demonstrated that low-dose vitamin K was not associated with thromboembolism rate (risk ratio [RR] = 0.94; 95% CI: 0.19-4.55) major bleeding rate (RR = 0.58; 95% CI: 0.07-4.82), and minor bleeding rate (RR = 0.60; 95% CI: 0.07-5.09). Subgroup and sensitivity analysis demonstrated the nonsignificant effect of low-dose vitamin K on the risk of thromboembolism. Publication bias was not apparent, according to Begg's test and Egger's test (P = .090 and 0.134, respectively). CONCLUSION The current evidence does not support the role of low-dose vitamin K as a trigger of thromboembolism in supratherapeutic INR patients with mechanical heart valves. Nevertheless, more well-designed studies with larger sample sizes are required to justify this research question.
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2.
Efficacy of pharmacologic treatment for treating gastrointestinal angiodysplasias-related bleeding: a systematic review and meta-analysis
Gkolfakis P, Fostier R, Tziatzios G, Lazaridis N, Fernandez Y Viesca M, Facciorusso A, Despott E, Triantafyllou K, Devière J, Arvanitakis M
European journal of gastroenterology & hepatology. 2022
Abstract
INTRODUCTION We evaluated the efficacy of pharmacologic treatments for patients with overt or occult bleeding due to gastrointestinal angiodysplasias (GIADs). METHODS A systematic computer-aided literature search across Medline, Cochrane, Scopus and Embase databases was performed. Studies evaluating pharmacologic treatments for patients presenting with GIADs-related overt or occult bleeding were included. Post-treatment rebleeding was the primary outcome. Need for red blood cells (RBC) transfusion, post-treatment hemoglobin levels and adverse events rate comprised secondary outcomes. Results are presented as odds ratio (OR), mean difference (MD) or pooled rates (%) with 95% confidence intervals (95%CI). RESULTS Four types of pharmacologic treatment were identified (25 studies): somatostatin analogs, hormonal therapy, thalidomide and angiogenesis inhibitors. Pharmacologic treatment of any kind led to significantly reduced bleeding episodes [OR (95% CI), 0.08 (0.04-0.18)]. No pharmacologic treatment was superior to others (P = 0.46). Overall, pooled rebleeding rate post-treatment was 34% (26-43%). Similarly, significantly fewer patients required RBC transfusion during the post-treatment period [0.03 (0.03-0.07)], with no differences among various treatments (P = 0.83), yielding an overall pooled transfusion rate of 33% (19-46%). Administration of pharmacological treatment led to significant improvement in terms of hemoglobin levels [MD (95% CI), 3.21 g/dL (2.42-3.99)]. The pooled rate of adverse events was 32% (22-42%). CONCLUSION In patients with GIADs administration of any pharmacologic treatment significantly decreases rebleeding episodes and transfusions leading to higher hemoglobin values. One-third of them experience at least one adverse event related to the treatment.
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3.
Beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis
Cifuentes LI, Gattini D, Torres-Robles R, Gana JC
The Cochrane database of systematic reviews. 2021;1:Cd011973
Abstract
BACKGROUND Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. Variceal haemorrhage commonly occurs in children with chronic liver disease or portal vein thrombosis. Therefore, prevention is important. Band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding in children. However, primary prophylaxis is not the current standard of care in paediatric patients because it is unknown whether those treatments are of benefit or harm when used for primary prophylaxis in children and adolescents. OBJECTIVES To determine the benefits and harms of beta-blockers compared with placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, LILACS, and Science Citation Index Expanded (April 2020). We screened the reference lists of the retrieved publications and manually searched the main paediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstract books from 2008 to December 2019. We searched clinicaltrials.gov, the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) for ongoing clinical trials. We imposed no language or document type restrictions on our search. SELECTION CRITERIA We planned to include randomised clinical trials, irrespective of blinding, language, or publication status to assess benefits and harms. We included observational studies, retrieved with the searches for randomised clinical trials, for a narrative report of harm. DATA COLLECTION AND ANALYSIS We planned to summarise data from randomised clinical trials by standard Cochrane methodologies. We planned to asses risk of bias and use GRADE to assess the certainty of evidence. Our primary outcomes were all-cause mortality, serious adverse events and liver-related morbidity, and health-related quality of life. Our secondary outcomes were oesophageal variceal bleeding and adverse events not considered serious. We planned to use intention-to-treat principle. We planned to analyse data with RevMan Analysis. MAIN RESULTS We found no randomised clinical trials that assessed beta-blockers compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We found four observational studies that reported on harms. As a systematic search for observational studies was not planned, we only listed the reported harms in a table. AUTHORS' CONCLUSIONS Randomised clinical trials assessing the benefits or harms of beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking. Therefore, trials with adequate power and proper design, assessing the benefits and harms of beta-blockers versus placebo on patient-relevant clinical outcomes, such as mortality, quality of life, failure to control variceal bleeding, and adverse events are needed. Unless such trials are conducted and the results become published, we cannot make any conclusions regarding the benefits or harms of the two interventions.
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4.
Beta-Blockade in Aneurysmal Subarachnoid Hemorrhage: a Systematic Review and Meta-Analysis
Ramesh AV, Banks CFK, Mounstephen PE, Crewdson K, Thomas M
Neurocritical care. 2020
Abstract
BACKGROUND/OBJECTIVE Sympathetic nervous system activation after aneurysmal subarachnoid hemorrhage (aSAH) is associated with complications and poor outcome. In this systematic review and meta-analysis, we investigate the effect of beta-blockers on outcome after aSAH. METHODS The review was prospectively registered with PROSPERO (CRD42019111784). We performed a systematic literature search of MEDLINE, EMBASE, the Cochrane Library, published conference proceedings, and abstracts. Eligible studies included both randomized controlled trials and observational studies up to October 2018, reporting the effect of beta-blocker therapy on the following outcomes in aSAH: mortality, vasospasm, delayed cerebral ischemia, infarction or stroke, cardiac dysfunction, and functional outcomes. Studies involving traumatic SAH were excluded. Citations were reviewed, and data extracted independently by two investigators using a standardized proforma. RESULTS We identified 819 records with 16 studies (four were randomized controlled trials) including 6702 patients selected for analysis. Exposure to beta-blockade either before or after aSAH was associated with a significant reduction in unadjusted mortality (RR 0.63, 95% CI 0.42-0.93, p = 0.02). A significant reduction in unadjusted mortality was also seen in prospective trials of post-event beta-blockade (RR 0.51, 95% CI 0.28-0.93, p = 0.03). Statistically significant differences were not seen for other outcomes investigated. CONCLUSIONS In adult patients with aSAH, beta-blocker therapy is associated with a mortality benefit. Studies are generally of a low quality with considerable clinical heterogeneity. Prospective large interventional trials with patient centered outcomes are required to validate this finding.
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5.
Angiotensin II antagonists and gastrointestinal bleeding in left ventricular assist devices: A systematic review and meta-analysis
Kittipibul V, Vutthikraivit W, Kewcharoen J, Rattanawong P, Tantrachoti P, Putthapiban P, Nair N
The International journal of artificial organs. 2020;:391398820951811
Abstract
Gastrointestinal bleeding (GIB) especially from arteriovenous malformations (AVM) remains one of the devastating complications following continuous-flow left ventricular device (CF-LVAD) implantation. Blockade of angiotensin II pathway using angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) was reported to mitigate the risk of GIB and AVM-related GIB by suppressing angiogenesis. We performed a systematic review and meta-analysis to evaluate the association between ACEI/ARB treatment and GIB in CF-LVAD population. Comprehensive literature search was performed through December 2019. We included studies reporting risk of GIB and/or AVM-related GIB events in LVAD patients who received ACEI/ARB with those who did not. Data from each study were combined using the random-effects to calculate odd ratios and 95% confidence intervals. Three retrospective cohort studies were included in this meta-analysis involving 619 LVADs patients (467 patients receiving ACEI/ARB). The use of ACEI/ARB was statistically associated with decreased incidence of overall GIB (pooled OR 0.35, 95% CI 0.22-0.56, I(2) = 0.0%, p < 0.001). There was a non-significant trend toward lower risk for AVM-related GIB in patients who received ACEI/ARB (pooled OR 0.46, 95% CI 0.19-1.07, I(2) = 51%, p = 0.07). Larger studies with specific definitions of ACEI/ARB use and GIB are warranted to accurately determine the potential non-hemodynamic benefits of ACEI/ARB in CF-LVAD patients.
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6.
Targeting High Mobility Group Box 1 in Subarachnoid Hemorrhage: A Systematic Review
Muhammad S, Chaudhry SR, Kahlert UD, Lehecka M, Korja M, Niemela M, Hanggi D
Int J Mol Sci. 2020;21(8)
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) is a complex and potentially deadly disease. Neurosurgical clipping or endovascular coiling can successfully obliterate ruptured aneurysms in almost every case. However, despite successful interventions, the clinical outcomes of aSAH patients are often poor. The reasons for poor outcomes are numerous, including cerebral vasospasm (CVS), post-hemorrhagic hydrocephalus, systemic infections and delayed cerebral ischemia. Although CVS with subsequent cerebral ischemia is one of the main contributors to brain damage after aSAH, little is known about the underlying molecular mechanisms of brain damage. This review emphasizes the importance of pharmacological interventions targeting high mobility group box 1 (HMGB1)-mediated brain damage after subarachnoid hemorrhage (SAH) and CVS. We searched Pubmed, Ovid medline and Scopus for "subarachnoid hemorrhage" in combination with "HMGB1". Based on these criteria, a total of 31 articles were retrieved. After excluding duplicates and selecting the relevant references from the retrieved articles, eight publications were selected for the review of the pharmacological interventions targeting HMGB1 in SAH. Damaged central nervous system cells release damage-associated molecular pattern molecules (DAMPs) that are important for initiating, driving and sustaining the inflammatory response following an aSAH. The discussed evidence suggested that HMGB1, an important DAMP, contributes to brain damage during early brain injury and also to the development of CVS during the late phase. Different pharmacological interventions employing natural compounds with HMGB1-antagonizing activity, antibody targeting of HMGB1 or scavenging HMGB1 by soluble receptors for advanced glycation end products (sRAGE), have been shown to dampen the inflammation mediated brain damage and protect against CVS. The experimental data suggest that HMGB1 inhibition is a promising strategy to reduce aSAH-related brain damage and CVS. Clinical studies are needed to validate these findings that may lead to the development of potential treatment options that are much needed in aSAH.
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7.
Systematic Review and Meta-Analysis of Randomized Controlled Trials of Liangxue Tongyu Formula on Patients With Acute Intracerebral Hemorrhage
Jiang C, Yang X, Dong J, Li G
Front Pharmacol. 2020;11:437
Abstract
Background: As a traditional Chinese medicine (TCM) prescription for acute stroke, Liangxue Tongyu formula (LXTYF) was widely used as auxiliary treatment measure in some clinical practice. This study aimed to evaluate the clinical efficacy and safety of LXTYF combined western conventional medicine (WCM) with WCM only for acute intracerebral hemorrhage (ICH). Methods: We systematically searched PubMed, Embase, Cochrane Library, CMB (Chinese biomedicine database), CNKI (China National Knowledge Infrastructure), WanFang, and VIP until August 2019 to confirm relevant randomized controlled trials (RCTs) compared the combination of LXTYF and WCM with WCM alone for the treatment of acute ICH. Two investigators independently assessed the risk of bias, and extracted and analyzed the data from the identified studies using RevMan 5.3.0 software following Cochrane's standard and PRISMA guidelines. The herbal compositions of LXTYF were also assessed. Results: 15 RCTs were identified, totally recruiting 1648 patients with acute intracerebral hemorrhage. Compared with the WCM alone, the combination therapy of LXTYF with WCM could improve the clinical effective rate (RR, 1.21; 95% CI, 1.15-1.25, P < 0.05) and ADL score (MD, 18.09; 95% CI, 12.11-24.07; P < 0.05), and reduce syndrome scores of the TCM (MD, -4.11; 95% CI, -4.69 to -3.53; P < 0.05) and the Glasgow outcome score(GOS) (MD=0.43, 95%CI: 0.06 to 0.79, P=0.02) Moreover, there was no sufficient evidence to indicate the adverse effects would increase compared with WCM alone. Conclusion: Based on current evidence, we concluded that the combined therapy had some benefits in treating acute intracerebral hemorrhage. However, considering the potential biases and limitations of our study, additional large, high-quality RCTs are required in the future to confirm or refute the effects of LFTYF combined with WCM in acute stroke.
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8.
Role of Xingnaojing Injection in treating acute cerebral hemorrhage: A systematic review and meta-analysis
Ma X, Wang T, Wen J, Wang J, Zeng N, Zou W, Yang Y
Medicine (Baltimore). 2020;99(15):e19648
Abstract
BACKGROUND Xingnaojing injection (XNJi) is widely used for acute cerebral hemorrhage. However, the efficacy of XNJi for acute cerebral hemorrhage has not been comprehensively proved by systematic analysis yet. Therefore, it is essential to evaluate the efficacy and safety of XNJi in an evidence-based method. METHODS Six databases were searched with XNJi used for acute cerebral hemorrhage in randomized controlled trials (RCTs). Meta-analysis was performed by Review Manager 5.3. The efficacy rate, brain edema, cerebral hematoma, neurological deficit score, hs-crp, Glasgow Coma Scale (GCS), and activities of daily living (ADL) were systematically evaluated. The Cochrane risk of bias was used to evaluate the methodological quality of eligible studies. RESULTS This study is registered with PROSPERO (CRD42018098737). Twenty-nine studies with a total of 2638 patients were included in this meta-analysis. Compared with conventional treatment, XNJi got higher efficacy rate (OR = 3.37, 95% CI [2.65, 4.28], P < .00001). Moreover, XNJi showed significant enhancement of efficacy rate via subgroup analysis in course and dosage. In addition, XNJi demonstrated significant improvement in Chinese stroke scale (CSS) and National Institutes of Health Stroke Scale (NHISS) (mean difference [MD] = -4.74, 95% CI [-5.89, -3.60], P < .00001; MD = -4.45, 95% CI [-5.49, -3.41], P < .00001), GCS (MD = 2.72, 95% CI [2.09, 3.35], P < .00001). It also remarkably decreased the level of hs-crp (MD = -6.50, 95% CI [-7.79, -5.21], P < .00001), enhanced ADL (MD = 20.38, 95% CI [17.98, 22.79], P < .00001), and alleviated hematoma and edema (MD = -2.53, 95% CI [-4.75, -0.31] P < .05; MD = -1.74 95% CI [-2.42, -1.07] P < .00001) compared with conventional treatment. CONCLUSION XNJi is effective in treating acute cerebral hemorrhage with significant improvement of CSS, NHISS and impairment of hs-crp, hematoma, and edema compared with conventional treatment. Moreover, XNJi got remarkable efficacy at the dose of 20, 30, 60 mL and from 7 to 28 days. No serious adverse reactions occurred. These results were mainly based on small-sample and low-quality studies. Therefore, more rigorous, large-scale RCTs were further needed to confirm its efficacy, safety, and detailed characteristic of application.
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9.
Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI
Marquis-Gravel G, Dalgaard F, Jones AD, Lokhnygina Y, James SK, Harrington RA, Wallentin L, Steg PG, Lopes RD, Storey RF, et al
J Am Coll Cardiol. 2020;76(2):162-171
Abstract
BACKGROUND The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored. OBJECTIVES The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality. METHODS In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI. RESULTS Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher <30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696). CONCLUSIONS Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.
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10.
Prevention of Non-Surgical Bleeding by Management of HeartMate II Patients without Antiplatelet Therapy
Jorde U, Katz JN, Colombo PC, Stulak JM, Crandall D, Franke A, Adamson RM
J Heart Lung Transplant. 2020;39(4s):S48-s49
Abstract
PURPOSE Optimization of antithrombotic therapy, with the goal of minimizing bleeding without adversely affecting thromboembolic (TE) rates, is a major priority of the MCS field. We evaluated the safety and efficacy of managing HeartMate II (HM II) patients without antiplatelet therapy. METHODS Prospective, multicenter, randomized, double-blind placebo-controlled trial of aspirin (ASA) 81 mg daily in subjects ≥50 years of age receiving warfarin (INR of 2.0-2.5) after initial HM II implantation. Subjects were placed on study drug once hemodynamic stability was achieved, no later than POD 15. Primary efficacy endpoint was the composite incidence of non-surgical bleeding at 6 months. Primary safety endpoint was the composite incidence of pump thrombosis and stroke 6 months post implant. Descriptive endpoints included hemocompatibility related adverse events at 12 months. The study was stopped due to futility given competing enrollment in another study. RESULTS 65/72 (31 placebo, 34 ASA) subjects enrolled within 48 hours of HM II implant met criteria for initiation of the study drug. At 6 and 12 months, respectively, 47 and 35 subjects remained on study drug. Study discontinuation was due to death (Placebo: 8.6% vs. ASA: 8.1%), transplant/explant (Placebo: 8.6% vs. ASA: 10.8 %), or withdrawal (Placebo: 34.3% vs. ASA: 32.4%) and was comparable between groups. In an as-treated analysis of the primary endpoints, at 6 months, the rates of nonsurgical bleeding (Placebo: 38 [21.6 - 55.9] %; ASA: 44 [27.4 - 60.8] %) and TE events (Placebo: 12.9 [1.1 - 24.7] %; ASA: 8.8 [0.0 - 18.4] %,) did not differ between groups. At 12 months, more major bleeding events had occurred in the ASA group compared to the placebo group (Placebo: 38.7 [21.6 - 55.9] %; ASA: 64.7 [48.6 - 80.8] %), but stroke rates remained comparable (Placebo: 19.4 [5.4 - 33.3] %; ASA: 20.6 [7.0 - 34.2] %). CONCLUSION In the first prospective, randomized double blind placebo-controlled study of an ASA free regimen in patients on durable LVAD support receiving warfarin, we did not observe increased rates of TE events. Our findings are only applicable to the HMII device and significantly limited by an early study stop. However, they provide supportive rationale for the study of antiplatelet free regimen in contemporary LVADs, specifically those with decreased device thrombosis.